JP2024099551A - Method for producing aminodiaryl ether and aminodiaryl ether hydrochloride - Google Patents

Abstract

【選択図】なしThe present invention provides a method for preparing a specific amine hydrochloride.
The method comprises reducing a compound of formula (IIa) with hydrogen in the presence of a Pd catalyst and a particular solvent to form a compound of formula (Ia), which is then reacted with less than about 1.5 molar equivalents of hydrochloric acid.

[Selection diagram] None

Description

The present invention relates to a method useful for the preparation of aminodiaryl ethers of formula (I), in particular 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)).

The present invention further relates to hydrochlorides of compounds of formula (I), particularly the monohydrochlorides of compounds of formula (I), and to methods useful for the preparation of compounds of formula (I), particularly the monohydrochlorides of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)).

The compounds of formula (I), which are modulators of the Notch signalling pathway useful for the treatment and/or prevention of cancer, in particular for the treatment and/or prevention of Notch-dependent cancers, can be prepared using the method disclosed in WO 2013/093885. The method disclosed in WO 2013/093885 has the disadvantages, among others, that (i) the compounds of formula (I) obtained by said method are contaminated with the catalyst used, and (ii) side reactions occur, further contaminating the compounds of formula (I) with by-products. These disadvantages affect, for example, the physical appearance and solubility of the compounds of formula (I), as well as subsequent manufacturing steps such as grinding. In conclusion, the methods described in WO 2013/093885 are not suitable for large-scale manufacturing of pharmaceutical grade compounds of formula (I). It would therefore be beneficial to develop alternative or improved methods for the manufacture of compounds of formula (I) that do not suffer from some or all of these disadvantages.

Surprisingly, it has now been found that contamination of compounds of formula (I) can be eliminated by preparing them via a process involving catalytic hydrogenation using a palladium catalyst in a solvent that is a polar aprotic solvent or a C3-C10 alcohol. The process of the present invention has been found to be reliable and applicable on an industrial scale, and the compounds of formula (I) achieved by the process of the present invention consistently have unprecedentedly high levels of purity (99.9% purity as determined by HPLC, Pd content <1 ppm as determined by elemental analysis).

The inventors have surprisingly found that when the compounds of formula (I) are converted to their hydrochloride salts, stable salts are obtained, whereas all attempts to form other acid addition salts fail. The inventors have further surprisingly found that when the compounds of formula (I) are converted to their monohydrochloride salts, the purity level is further increased in that, regardless of the analytical purity level, the monohydrochloride salts are typically obtained as colorless crystalline solids, whereas the color of the respective free bases varies from batch to batch (ranging from colorless to reddish).

Compounds disclosed in WO 2013/093885, such as 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)), have a very low melting point, e.g., 92.0° C. (FIG. 2), which poses certain risks with respect to the physical stability of the compound during manufacture, grinding, storage, and processing into pharmaceutical formulations. However, surprisingly, the monohydrochloride salt of the compound of formula (I), e.g., 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride (formula (Ia)), has a significantly higher melting point than the free base (e.g., 173° C., FIG. 1). Thus, the monohydrochloride salt of the compound of formula (I) surprisingly has improved properties, such as a higher melting point, improved solubility in aqueous media, and separate polymorphs by XRPD, relative to the free base form of the compound of formula (I).

In view of these surprising findings, namely the high level of purity of the compound of formula (I) achieved by the process of the present invention, and the favorable properties of the hydrochloride salt of the compound of formula (I), particularly the monohydrochloride salt of the compound of formula (I), the inventors provide the present invention in its following aspects:

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物を製造するための方法であって、
式（ＩＩ）

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１１及びＲ^２２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３３及びＲ^４４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）
の化合物を、パラジウム触媒と、溶媒であって、極性の非プロトン性溶媒又はＣ３－Ｃ１０アルコールである溶媒の存在下で、水素で還元して、前記式（Ｉ）の化合物を形成することを含む、方法を提供する。 In a first aspect, the present invention provides a method for producing a composition comprising the steps of:
Formula (I)

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, comprising the steps of:
Formula (II)

wherein X is selected from O and NH; and Y ¹ , Y ² , and Y ³ are each independently selected from N and CH; and R ¹¹ and R ²² are each independently selected from H, C1-C10 alkyl, and C3-C12 cycloalkyl; and R ³³ and R ⁴⁴ are each independently selected from H, halogen, and C1-C10 alkyl.
with hydrogen in the presence of a palladium catalyst and a solvent which is a polar aprotic solvent or a C3-C10 alcohol to form a compound of formula (I).

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物の塩酸塩を製造するための方法であって、前記式（Ｉ）の化合物を塩酸と反応させることを含む方法を提供する。 In a second aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, the process comprising reacting said compound of formula (I) with hydrochloric acid.

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物の一塩酸塩を製造するための方法であって、前記式（Ｉ）の化合物を１．５モル当量未満の塩酸と反応させることを含む方法を提供する。 In a third aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, the process comprising reacting said compound of formula (I) with less than 1.5 molar equivalents of hydrochloric acid.

In a fourth aspect, the present invention provides a hydrochloride salt of a compound of formula (I) as defined herein.

In a fifth aspect, the present invention provides a monohydrochloride salt of a compound of formula (I) as defined herein.

In a sixth aspect, the present invention provides the hydrochloride salt of a compound of formula (I) as defined herein for use as a medicament.

In a seventh aspect, the present invention provides a monohydrochloride salt of a compound of formula (I) as defined herein for use as a medicament.

In an eighth aspect, the present invention provides the hydrochloride salt of a compound of formula (I) as defined herein for use in a method for the treatment and/or prophylaxis of cancer.

In a ninth aspect, the present invention provides a monohydrochloride salt of a compound of formula (I) as defined herein for use in a method for the treatment and/or prophylaxis of cancer.

The present invention will now be described in detail with reference to the accompanying drawings, in which:
1 shows a differential scanning calorimetry thermogram (DSC) of the monohydrochloride salt of the compound of formula (Ia), i.e., 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride. The DSC thermogram shows that 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride has a melting point with an onset of 170.9° C. and a peak at 173.4° C. 1 shows a DSC thermogram for the compound of formula (Ia), i.e., 6-(4-(tert-butyl)phenoxy)pyridin-3-amine. The DSC thermogram shows a melting point for the compound of formula (Ia) with an onset at 90.8° C. and a peak at 92.0° C. 1 shows an X-ray powder diffraction (XRPD) diffractogram of the monohydrochloride salt of compound of formula (Ia), namely 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride salt. FIG. 2 shows the HPLC chromatogram of the compound of formula (Ia), namely 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (purity: 99.9%) obtained by the method of the present invention (see Example 3A). FIG. 2 shows a reference HPLC chromatogram of the compound of formula (Ia), i.e., 6-(4-(tert-butyl)phenoxy)pyridin-3-amine, obtained by the method described in WO 2013/093885 (Example 2). FIG. 1 shows a DSC thermogram of the material obtained when 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia)) is reacted with more than 1.5 molar equivalents of hydrochloric acid (Example 5). The DSC thermogram shows that the material does not have a sharp melting point, suggesting the presence of at least two species.

The present invention will now be described and exemplified in further detail.
[Definition]
The term "about" means ±10% of a given measurement.

The term "polar aprotic solvent" refers to a solvent that does not contain an acidic hydrogen (Morrison and Boyd, Organic Chemistry 3rd ed., 31 (1974)) and has a polarity according to the E _T (30) scale between about 36 kcal/mol and about 49 kcal/mol (C. Reichardt, Chem. Rev. 1994, 94, 2319 - 2358; C. Reichardt, G. Schafer, Liebigs Ann. 1995, 1579-1582; R. Eberhardt, S. Lobbecke, B. Neidhart, C. Reichardt, Liebigs Ann. /Recueil 1997, 1195-1199; C. Reichardt, Green Chem. 2005, 7, 339-351; VG Machado, RI Stock, C. Reichardt, Chem. Rev. 2014, 114, 10429-10475). Proton donating or proton accepting interactions are usually maximized when the atom bonded to the proton is nitrogen or oxygen. This property is attributed to hydrogen bonding. In general, hydrogen bond strength increases with increasing acidity of the proton donating group and increasing basicity of the proton accepting group. Polar aprotic solvents suitable for use in this invention are those solvents that do not contain acidic or basic functional groups and do not decompose into acids or bases, including, but not limited to, ketones, nitriles, substituted aromatics such as halogenated aromatics, amides, sulfoxides, alkyl carbonates, chlorinated aliphatics, aromatic aldehydes, sulfones, esters, and the like, or mixtures thereof. Preferred polar aprotic solvents for use in this invention include, but are not limited to, acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and mixtures thereof. A variety of other solvents having the above polar and aprotic characteristics will be known to those skilled in the art.

The term "C3-C10 alcohol" refers to an unsubstituted straight or branched alkanol group containing 3-10 carbon atoms, preferably an unsubstituted straight or branched alkanol group containing 3-5 carbon atoms, such as 1-propanol, 2-propanol, 2-butanol, 2-methyl-1-propanol, or 2-methylpropan-2-ol, more preferably 2-butanol or 2-propanol, and most preferably 2-propanol.

The term "non-polar solvent" refers to a solvent having a polarity according to the E _T (30) scale of less than about 35 kcal/mol. Preferred non-polar solvents for use in this invention include, but are not limited to, pentane, hexane, heptane, cyclohexane and toluene, especially heptane. When the non-polar solvent is, for example, a C5-C8-alkane, such as pentane, hexane or heptane, said C5-C8-alkane can be isomerically pure (e.g., n-pentane, n-hexane or n-heptane) or a random mixture of structural isomers.

The term "protic solvent" refers to a solvent that contains a proton-donating group. A non-limiting example of a protic solvent is water.

The term "Tout" refers to the external temperature measured outside the reactor, and the term "Ti" refers to the internal temperature measured inside the reactor. When a reaction temperature is given without specifying "Tout" or "Ti", it is understood that the temperature is measured outside the reactor.

The term "alkyl" refers to an unsubstituted linear or branched alkyl group, preferably an unsubstituted linear or branched alkyl group containing 1-10 carbon atoms ("C1-C10 alkyl"), more preferably an unsubstituted linear or branched alkyl group containing 3-8 carbon atoms ("C3-C8 alkyl"). Non-limiting examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, and 1,1-dimethylbutyl. A particularly preferred alkyl group is tert-butyl.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "cycloalkyl" refers to an unsubstituted monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group of 3 to 12 carbon atoms ("C3-C12 cycloalkyl"), preferably 5 to 10 carbon atoms ("C5-C10 cycloalkyl"). Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Particularly preferred cycloalkyl groups are cyclohexyl and adamantyl.

The term "activated carbon" refers to a form of carbon that has been engineered to have small, low volume pores that increase the surface area available for adsorption or chemical reactions. Activated carbon has a surface area of over 500 ^m2 /g. Typically, activated carbon has a surface area of about 1000 ^m2 /g, but can be up to 3000 ^m2 /g. Non-limiting examples of activated carbon are those with an iodine absorption of >70 mL/g (0.05 mole _I2 /I) and/or a methylene blue absorption of >12 mL/0.1 g (0.15% solution) or an iodine absorption of 1200 mg/g and/or a methylene blue absorption of 255 mg/g.

The term "base" refers to a compound that deprotonates another compound when reacted with it. Bases suitable for use in accordance with this disclosure include, but are not limited to, for example, tertiary amines, organolithium compounds, and basic alkali metal salts and hydrides. Examples of tertiary amines include triethylamine, N-methylmorpholine, and diisopropylethylamine. Examples of organolithium compounds include methyllithium (CH ₃ Li, MeLi), n-butyllithium (n-BuLi), sec-butyllithium (sec-BuLi), and tert-butyllithium (tert-BuLi). Examples of basic alkali metal hydrides and salts include, for example, sodium hydride (NaH), potassium hydride (KH), sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), sodium bicarbonate (NaHCO ₃ ), sodium and potassium alkoxides including, but not limited to, sodium and potassium t-butoxide, propoxide, i-propoxide, ethoxide, methoxide, and the like, sodium amide (NaNH ₂ ), potassium amide (KNH ₂ ), and the like. Preferred bases are MeLi, K ₂ CO ₃ , and Na ₂ CO ₃ .

The term "hydrochloride salt" refers to a compound of formula (I) or (Ia), respectively, where said compound of formula (I) or (Ia) is protonated and the counterion is chloride (Cl- ⁾ , and includes mono- and/or dichloride salts, particularly mixed mono- and dichloride salts.

The term "monohydrochloride salt" refers to a compound of formula (I) or (Ia), respectively, that is protonated once and the counterion is chloride (Cl ^- ). Thus, the stoichiometry of a monoprotonated compound of formula (I) or (Ia) to chloride is 1:1.

The term "purity" is expressed in percentage (%) and is calculated from an HPLC chromatogram recorded at 220 nm according to the following formula:
Purity of the compound of formula (I)=(A _I /A _x )×100;
where A _I is the area of the peak corresponding to a compound of formula (I), e.g., a compound of formula (Ia), and A _x is the sum of the areas of all other peaks observed in the HPLC chromatogram.

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物を製造するための方法であって、
式（ＩＩ）

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１１及びＲ^２２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３３及びＲ^４４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）
の化合物を、パラジウム触媒と、溶媒であって、極性の非プロトン性溶媒又はＣ３－Ｃ１０アルコールである溶媒の存在下で、水素で還元して、前記式（Ｉ）の化合物を形成することを含む、方法を提供する。 Process for preparing compounds of formula (I)
In a first aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, comprising the steps of:
Formula (II)

wherein X is selected from O and NH; and Y ¹ , Y ² , and Y ³ are each independently selected from N and CH; and R ¹¹ and R ²² are each independently selected from H, C1-C10 alkyl, and C3-C12 cycloalkyl; and R ³³ and R ⁴⁴ are each independently selected from H, halogen, and C1-C10 alkyl.
with hydrogen in the presence of a palladium catalyst and a solvent which is a polar aprotic solvent or a C3-C10 alcohol to form a compound of formula (I).

In one embodiment, the method according to the first aspect of the present invention is provided, in which the palladium catalyst is palladium on activated carbon.

In a preferred embodiment, the method according to the first aspect of the present invention is provided, in which the palladium catalyst is palladium on activated carbon selected from palladium on activated carbon containing about 10% wt/wt palladium and palladium on activated carbon containing about 5% wt/wt palladium, in particular palladium on activated carbon containing about 5% wt/wt palladium.

In one embodiment, said reduction of a compound of formula (II) to provide a compound of formula (I) is
There is provided a process according to a first aspect of the present invention comprising the steps of: (a) providing a solution of a compound of formula (II) in a solvent, wherein the solvent is a polar aprotic solvent or a C3-C10 alcohol; followed by (b) adding a palladium catalyst to the solution of step (a); and (c) contacting the mixture obtained in step (b) with hydrogen, wherein the palladium catalyst added in step (b) is added as a dry powder or as a suspension in the solvent used in step (a), preferably as a suspension in the solvent used in step (a).

In a further embodiment, there is provided a method according to the first aspect of the invention, wherein the amount of palladium relative to the compound of formula (II) is less than 7 mol%, preferably less than about 6 mol%, more preferably less than about 5 mol%, more preferably less than about 4 mol%, more preferably less than about 3 mol%, more preferably less than about 2 mol%, in particular about 1.25 mol%.

In a further embodiment, there is provided a method according to the first aspect of the invention, wherein the amount of palladium relative to the compound of formula (II) is less than 7 mol% and 1 mol% or more, preferably less than about 6 mol% and 1 mol% or more, more preferably less than about 5 mol% and 1 mol% or more, more preferably less than about 4 mol% and 1 mol% or more, more preferably less than about 3 mol% and 1 mol% or more, more preferably less than about 2 mol% and 1 mol% or more, especially about 1.25 mol%.

In a preferred embodiment, there is provided a method according to the first aspect of the present invention, wherein the solvent is selected from 2-propanol, acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and mixtures thereof.

In a further preferred embodiment, the method according to the first aspect of the present invention is provided, wherein the solvent is selected from 2-propanol, acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, and mixtures thereof.

In a more preferred embodiment, the method according to the first aspect of the present invention is provided, wherein the solvent is a polar aprotic solvent.

In an even more preferred embodiment, the method according to the first aspect of the present invention is provided, wherein the solvent is selected from acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and mixtures thereof.

In an even more preferred embodiment, the method according to the first aspect of the invention is provided, wherein the solvent is selected from acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, and mixtures thereof.

In a particularly preferred embodiment, the method according to the first aspect of the present invention is provided, in which the solvent is ethyl acetate or 2-propanol.

In a more particularly preferred embodiment, the method according to the first aspect of the present invention is provided, in which the solvent is ethyl acetate.

The inventors have surprisingly found that the method according to the invention allows for shorter reaction times than the prior art method described in WO 2013/093885.
Thus, in one embodiment there is provided a process according to the first aspect of the present invention, wherein the reduction of said compound of formula (II) to said compound of formula (I) is complete after 1-3 hours, preferably after 1.5-3 hours, more preferably after 2-3 hours, such as after 2.5 hours, preferably when carried out using 1.2 kg of compound of formula (II).
In a further embodiment, there is provided a process according to the first aspect of the present invention, wherein the reduction of said compound of formula (II) to said compound of formula (I) is complete after 0.5-1.5 hours, preferably after 40 minutes, preferably when carried out using 300 g of compound of formula (II).

In a further embodiment, there is provided a method according to the first aspect of the invention, further comprising contacting the compound of formula (I) with activated carbon.

In a further embodiment, there is provided a method according to the first aspect of the invention further comprising crystallizing the compound of formula (I).

In a preferred embodiment, there is provided a method according to the first aspect of the invention, further comprising contacting the compound of formula (I) with activated carbon; and crystallizing the compound of formula (I).

In a further embodiment, there is provided a method according to the first aspect of the invention, further comprising crystallizing the compound of formula (I), said crystallization comprising precipitating the compound of formula (I) in crystalline form from a solvent mixture comprising a solvent as described herein, preferably a polar aprotic solvent used in the reduction of the compound of formula (II), and a non-polar solvent.

In a preferred embodiment, there is provided a method according to the first aspect of the present invention, further comprising crystallizing the compound of formula (I), said crystallizing comprising precipitating the compound of formula (I) in crystalline form from a solvent mixture comprising ethyl acetate and heptane.

（上式中、Ｘ^１はＯＨ及びＮＨ_２から選択され；かつ
Ｒ^１１及びＲ^２２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル、及びＣ３－Ｃ１２シクロアルキルから独立して選択される）
の化合物を、式（ＩＶ）

（上式中、ＬＧは脱離基であり、かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^３３及びＲ^４４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）
の化合物と塩基の存在下で反応させて、式（ＩＩ）（式中、ＸはＯ又はＮＨであり；かつＲ^１１及びＲ^２２は、式（ＩＩＩ）の化合物について定義された通りであり；かつＲ^３３、Ｒ^４４、Ｙ^１、Ｙ^２及びＹ^３は、式（ＩＶ）の化合物について定義された通りである）の前記出発物質を形成することを含み；かつ場合によっては前記式（ＩＩ）の出発物質を結晶化させることを更に含む、方法によって得られる、本発明の第一の態様に係る方法が提供される。 In a further embodiment, the starting material of formula (II) is a compound of formula (III)

wherein X ¹ is selected from OH and NH ₂ ; and R ¹¹ and R ²² are each independently selected from H, C1-C10 alkyl, and C3-C12 cycloalkyl.
With a compound of formula (IV)

wherein LG is a leaving group; and Y ¹ , Y ² , and Y ³ are each independently selected from N and CH; and R ³³ and R ⁴⁴ are each independently selected from H, halogen, and C1-C10 alkyl.
in the presence of a base to form said starting material of formula (II), wherein X is O or NH; and R ¹¹ and R ²² are as defined for compounds of formula (III); and R ³³ , R ⁴⁴ , Y ¹ , Y ² and Y ³ are as defined for compounds of formula (IV); and optionally further comprising crystallizing said starting material of formula (II).

In one embodiment, the leaving group LG is selected from the group consisting of F, Cl, Br, mesylate, tosylate and triflate. Preferably, the leaving group LG is selected from the group consisting of F, Cl and Br.

In a preferred embodiment, there is provided a process according to a first aspect of the invention, wherein the starting material of formula (II) is obtained by a process comprising reacting a compound of formula (III) as defined above with a compound of formula (IV) as defined above in the presence of a base in a polar aprotic solvent, preferably selected from dimethylsulfoxide (DMSO), dimethylformamide (DMF) or mixtures thereof, most preferably DMSO, to form said starting material of formula (II).

In a preferred embodiment, there is provided a process according to the first aspect of the invention, wherein the starting material of formula (II) is obtained by a process comprising reacting a compound of formula (III) as defined above with a compound of formula (IV) as defined above in the presence of a base to form said starting material of formula (II) and optionally further comprising crystallizing said starting material of formula (II), said base being selected from the group consisting of potassium carbonate (K ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ), caesium carbonate (Cs ₂ CO ₃ )NEt ₃ , Hunigs base and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably selected from the group consisting of potassium carbonate (K ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ) and caesium carbonate (Cs ₂ CO ₃ ). More preferably, said base is potassium carbonate (K ₂ CO ₃ ).

In a further preferred embodiment, the method according to the first aspect of the invention is provided, wherein the starting material of formula (II) is obtained by a process comprising reacting a compound of formula (III) as defined above with a compound of formula (IV) as defined above in the presence of a base in a polar aprotic solvent, preferably selected from dimethylsulfoxide (DMSO), dimethylformamide (DMF) or a mixture thereof, most preferably in DMSO, to form said starting material of formula (II), and optionally further comprising crystallizing said starting material of formula (II), said crystallization comprising precipitating the starting material of formula (II) in crystalline form from a solvent mixture comprising a polar aprotic solvent and a non-polar solvent, preferably from a solvent mixture comprising ethyl acetate and heptane.

かつ前記式（ＩＩ）の化合物が、２－（４－（ｔｅｒｔ－ブチル）フェノキシ）－５－ニトロピリジン（式（ＩＩａ））であり、

かつ場合によっては、式（ＩＩａ）の出発物質が、４－（ｔｅｒｔ－ブチル）－フェノール（式（ＩＩＩａ））を

２－クロロ－５－ニトロ－ピリジン（式（ＩＶａ））と、

塩基の存在下で反応させて２－（４－（ｔｅｒｔ－ブチル）フェノキシ）－５－ニトロピリジン（式（ＩＩａ））を形成することを含み、場合によっては前記２－（４－（ｔｅｒｔ－ブチル）フェノキシ）－５－ニトロピリジン（式（ＩＩａ））を結晶化させることを更に含む方法によって得られる、本発明の第一の態様に係る方法が提供される。
よって、本発明は、式（Ｉａ）

の化合物を製造するための方法であって、パラジウム触媒と、極性の非プロトン性溶媒又はＣ３－Ｃ１０アルコールである溶媒の存在下で、式（ＩＩａ）の化合物を水素で還元して

前記式（Ｉａ）の化合物を形成することを含む、方法を提供する。 In a particularly preferred embodiment, the compound of formula (I) is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)),

and the compound of formula (II) is 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)),

And optionally, the starting material of formula (IIa) is 4-(tert-butyl)-phenol (formula (IIIa)).

2-chloro-5-nitro-pyridine (formula (IVa)),

There is provided a process according to a first aspect of the present invention, wherein the compound is obtained by a process comprising reacting in the presence of a base to form 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)), optionally further comprising crystallizing said 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)).
Thus, the present invention provides a compound of formula (Ia)

by reducing a compound of formula (IIa) with hydrogen in the presence of a palladium catalyst and a solvent which is a polar aprotic solvent or a C3-C10 alcohol.

forming a compound of formula (Ia)

In a further particularly preferred embodiment, said compound of formula (I) is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)); and the starting material of formula (II) is 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)); and the starting material of formula (IIa) comprises reacting 4-(tert-butyl)-phenol (formula (IIIa)) with 2-chloro-5-nitro-pyridine (formula (IVa)) in the presence of a base to form 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)); and There is provided a process according to a first aspect of the present invention, comprising crystallizing said 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)), wherein 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)) is precipitated in crystalline form from a solvent mixture comprising ethyl acetate and heptane.

In a further particularly preferred embodiment of the first aspect of the present invention, the present invention provides a process for preparing 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)), comprising reducing 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)) with hydrogen in the presence of palladium on activated carbon and ethyl acetate to form 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)).

In a further particularly preferred embodiment of the first aspect of the invention, the invention provides a method for preparing 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)) comprising reducing 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)) with hydrogen in the presence of palladium on activated carbon and ethyl acetate to form 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)); the amount of palladium relative to the compound of formula (IIa) is less than 7 mol%, preferably less than about 6 mol%, more preferably less than about 5 mol%, more preferably less than about 4 mol%, more preferably less than about 3 mol%, more preferably less than about 2 mol%, and especially about 1.25 mol%.

In a further particularly preferred embodiment of the first aspect of the invention, the invention provides a method for preparing 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)) comprising reducing 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)) with hydrogen in the presence of palladium on activated carbon and ethyl acetate to form 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)); the amount of palladium relative to the compound of formula (IIa) is less than 7 mol% and 1 mol% or more, preferably less than about 6 mol% and 1 mol% or more, more preferably less than about 5 mol% and 1 mol% or more, more preferably less than about 4 mol% and 1 mol% or more, more preferably less than about 3 mol% and 1 mol% or more, more preferably less than about 2 mol% and 1 mol% or more, especially about 1.25 mol%.

In a further particularly preferred embodiment of the first aspect of the present invention, the present invention comprises reducing 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)) with hydrogen in the presence of palladium on activated carbon and ethyl acetate to form 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)), wherein the reduction of said 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)) with hydrogen comprises
(a) providing a solution of 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (Formula (IIa)) in ethyl acetate; followed by (b) adding palladium on charcoal to the solution of step (a);
(c) contacting the suspension obtained in step (b) with hydrogen, wherein the palladium on activated carbon added in step (b) is added as a dry powder or as a suspension in ethyl acetate, preferably as a suspension in ethyl acetate.

Compounds of formula (I)
Preferably, the group _NH2 is in the 4th position (para) relative to the group X of the ring carrying the groups ^Y1 , ^Y2 and ^Y3 . Preferably, the group ^R1 or ^R2 is in the 3rd position (meta) or 4th position (para) relative to the group X of the ring without the groups ^Y1 , ^Y2 and ^Y3 , more preferably, ^R1 is in the 4th position (para) relative to the group X of the ring without the groups ^Y1 , ^Y2 and ^Y3 , while ^R2 is H, and even more preferably, ^R1 is H, while ^R2 is in the 4th position (para) relative to the group X of the ring without the groups ^Y1 , ^Y2 and ^Y3 . Preferably, the group ^R3 or ^R4 is in the 2nd position (ortho) relative to the group X of the ring carrying the groups ^Y1 , ^Y2 and ^Y3 (provided that ^Y2 and/or ^Y1 are C). More preferably, ^R3 is in the 2-position (ortho) relative to the group X of the ring carrying the groups ^Y1 , ^Y2 and ^Y3 (with the proviso that ^Y2 and/or ^Y1 are C) while ^R4 is H, even more preferably ^R3 is H while ^R4 is in the 2-position (ortho) relative to the group X of the ring carrying the groups ^Y1 , ^Y2 and ^Y3 (with the proviso that ^Y2 and/or ^Y1 are C). Preferably, the group ^R11 or ^R22 is in the 3-position (meta) or 4-position (para) relative to the group X of the ring not carrying the groups ^Y1 , ^Y2 and ^Y3 , while ^R22 is H, even more preferably ^R11 is H while ^R22 is in the 4-position (para) relative to the group X of the ring not carrying the groups ^Y1 , ^Y2 and ^Y3 . Preferably, the group R ³³ or R ⁴³ is in the 2-position (ortho) to the group X of the ring carrying the groups Y ¹ , Y ² and Y ³ (provided that Y ² and/or Y ¹ are C), more preferably R ³³ is in the 2-position (ortho) to the group X of the ring carrying the groups Y ¹ , Y ² and Y ³ while R ⁴⁴ is H, even more preferably R ³³ is H while R ⁴³ is in the 2-position (ortho) to the group X of the ring carrying the groups Y ¹ , Y ² and Y ³ (provided that Y ² and/or Y ¹ are C).

In a preferred embodiment, the method according to the first aspect of the present invention is provided, wherein for the compound of formula (I), X is O; and for the compound of formula (II), X is O.

In a further embodiment, for the compounds of formula (I),
The method according to the first aspect of the present invention is provided, wherein ^Y1 , ^Y2 , ^Y3 are each selected from N and CH, and at least one of ^Y1 , ^{Y2 ,} and ^Y3 is CH; and for the compound of formula (II), ^Y1 , ^Y2 , and ^Y3 are each selected from N and CH, and at least one of ^Y1 , Y2, and ^Y3 is CH.
In a further embodiment, for the compounds of formula (I),
The method according to the first aspect of the present invention is ^provided , wherein ^Y1 , ^Y2 , ^Y3 are each selected from N and CH, and at least one of Y1 and ^Y3 is CH; and for the compound of formula (II), ^Y1 , ^Y2 , and ^Y3 are each selected from N and CH, and at least one of ^Y1 and ^Y3 is CH.
In a preferred embodiment, for the compound of formula (I),
Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and for the compound of formula (II),
There is provided a method according to a first aspect of the present invention, wherein ^Y1 is selected from N and CH; and ^Y2 and ^Y3 are each CH.
In a more preferred embodiment, for the compound of formula (I),
Y ¹ is N; and Y ² and Y ³ are each CH; and for the compound of formula (II),
There is provided a method according to a first aspect of the present invention, wherein ^Y1 is N; and ^Y2 and ^Y3 are each CH.

In one embodiment, there is provided a method according to the first aspect of the present invention, wherein, for the compound of formula (I), R ¹ and R ² are each independently selected from H and C1-C10 alkyl; and, for the compound of formula (II), R ¹¹ and R ²² are each independently selected from H and C1-C10 alkyl.
In a further embodiment, there is provided a method according to the first aspect of the present invention, wherein, for said compound of formula (I), R ¹ and R ² are each independently selected from H and C3-C12 cycloalkyl; and, for said compound of formula (II), R ¹¹ and R ²² are each independently selected from H and C3-C12 cycloalkyl.
In a preferred embodiment, there is provided a process according to the first aspect of the present invention, wherein for said compound of formula (I), R ¹ is H and R ² is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and for said compound of formula (II), R ¹¹ is H and R ²² is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl.
In a further preferred embodiment, there is provided a process according to the first aspect of the present invention, wherein for said compound of formula (I), R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and for said compound of formula (II), R ¹¹ is H and R ²² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl.
In a particularly preferred embodiment, there is provided a process according to the first aspect of the invention, wherein for said compound of formula (I), R ¹ is H and R ² is tert-butyl; and for said compound of formula (II), R ¹¹ is H and R ²² is tert-butyl.

In one embodiment, there is provided a method according to the first aspect of the present invention, wherein, for the compound of formula (I), ^R3 and ^R4 are each independently selected from H and halogen; and, for the compound of formula (II), ^R33 and ^R44 are each independently selected from H and halogen.
In one embodiment, there is provided a process according to the first aspect of the invention, wherein, for said compound of formula (I), ^R3 and ^R4 are both halogen, preferably fluorine; and, for said compound of formula (II), ^R33 and ^R44 are both halogen, preferably fluorine.
In a preferred embodiment, there is provided a process according to the first aspect of the invention, wherein for said compound of formula (I), ^R3 is H and ^R4 is selected from H and halogen, preferably H and fluorine; and for said compound of formula (II), ^R33 is H and ^R44 is selected from H and halogen, preferably H and fluorine.
In a particularly preferred embodiment, there is provided a method according to the first aspect of the invention, wherein for said compound of formula (I), ^R3 and ^R4 are both H; and for said compound of formula (II), ^R33 and ^R44 are both H.

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each selected from N and CH, where at least one of Y ¹ , Y ² and Y ³ is CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each selected from N and CH, where at least one of Y ¹ and Y ³ is CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, C3-C8 alkyl and C5-C10 cycloalkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C3-C8 alkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C5-C10 cycloalkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is O; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C3-C8 alkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is O; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C5-C10 cycloalkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C3-C8 alkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C5-C10 cycloalkyl; and R ³ is H and R ⁴ is selected from H and halogen; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl, and adamantyl; and R ³ and R ⁴ are each independently selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ and R ⁴ are each independently selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is O; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is O; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is NH; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is NH; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is O; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In a preferred embodiment, for the compound of formula (I),
X is O; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is H; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is O; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is NH; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In one embodiment, for the compounds of formula (I),
X is NH; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In a preferred embodiment, for the compound of formula (I),
X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each selected from N and CH; and R ¹ is H and R ² is tert-butyl; and R ³ and R ⁴ are both H; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In a preferred embodiment, for the compound of formula (I),
X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is tert-butyl; and R ³ and R ⁴ are both H; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In a further preferred embodiment, for the compound of formula (I),
X is selected from O and NH; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is tert-butyl; and R ³ and R ⁴ are both H; and for the compound of formula (II),
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

In a further preferred embodiment, for the compound of formula (I),
X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ is H and R ² is tert-butyl; and R ³ and R ⁴ are both H; and for the compound of formula (II) above,
There is provided a method according to a first aspect of the invention, wherein X, ^Y1 , ^Y2 and ^Y3 are as defined for compounds of formula (I); and ^R11 is equal to ^R1 , ^R22 is equal to ^R2 , ^R33 is equal to ^R3 and ^R44 is equal to ^R4 of compounds of formula (I).

から選択され、かつ前記式（ＩＩ）の化合物が上に示された式（Ｖ）－（ＸＸ）の化合物のニトロアリール類似体から選択される、本発明の第一の態様に係る方法が提供される。 In a particularly preferred embodiment, the compound of formula (I) is

and said compound of formula (II) is selected from the nitroaryl analogues of compounds of formulae (V)-(XX) shown above.

In a further particularly preferred embodiment,
There is provided a method according to a first aspect of the present invention, wherein the compound of formula (I) is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia)); and the compound of formula (II) is 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa)).

Hydrochloride and monohydrochloride salts of the compound of formula (I)
The inventors have surprisingly found that when the compounds of formula (I) are converted to their hydrochloride salts, stable salts are obtained, but all attempts to form other acid addition salts have failed. The inventors have further surprisingly found that when the compounds of formula (I) are converted to their monohydrochloride salts, the purity level is further increased in that the monohydrochloride salts are typically obtained as colorless crystalline solids (see, for example, Example 4), while the color of each free base varies from batch to batch (ranging from colorless to reddish) regardless of the purity analysis level, which is consistently and highly reproducible (99.9% purity as determined by HPLC, Pd content <1 ppm as determined by elemental analysis). When providing active pharmaceutical ingredients (APIs) to the pharmaceutical industry, the consistent properties of the API, including its color, appearance, purity, solubility, and reproducibility of production, are of utmost importance. Thus, the highly pure, colorless and crystalline monohydrochloride salt of the compound of formula (I) has been found to be particularly useful as an API, and highly consistent in repeated large-scale multi-kg production.
Even more surprisingly, attempts to form other acid addition salts or the respective dihydrochloride salts were unsuccessful (see Example 5). For example, when more than 1.5 molar equivalents of hydrochloric acid were used to form the hydrochloride salt of the compound of formula (I), a mixture of monochloride and dichloride salts with unclear melting points was obtained (see Example 5 and Figure 6).

Thus, in one embodiment, there is provided a process according to the first aspect of the invention further comprising reacting a compound of formula (I) or (Ia) with hydrochloric acid, typically at least about 1.5 molar equivalents of hydrochloric acid, preferably at least about 1.5 molar equivalents and less than about 5 molar equivalents of hydrochloric acid, more preferably at least about 2 molar equivalents and less than about 3 molar equivalents of hydrochloric acid, even more preferably about 2.5 molar equivalents of hydrochloric acid, to form the hydrochloride salt of said compound of formula (I) or (Ia).
Thus, in one embodiment, there is provided a process according to the first aspect of the invention, further comprising reacting a compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, for example about 1.01 molar equivalents of hydrochloric acid to form a monohydrochloride salt of said compound of formula (I) or (Ia).

In a preferred embodiment, there is provided a method according to the first aspect of the invention, further comprising reacting a compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, typically less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, e.g., about 1.01 molar equivalents of hydrochloric acid to form a monohydrochloride salt of said compound of formula (I) or (Ia), wherein said reaction of the compound of formula (I) or (Ia) with hydrochloric acid is carried out in a protic solvent, preferably 2-propanol.

In one embodiment, there is provided a process according to the first aspect of the invention, further comprising reacting a compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and equal to or greater than about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, e.g. about 1.01 molar equivalents of hydrochloric acid to form a monohydrochloride salt of said compound of formula (I) or (Ia), followed by crystallizing said monohydrochloride salt.
In one embodiment, there is provided a process according to a first aspect of the present invention further comprising reacting a compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and equal to or greater than about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, for example about 1.01 molar equivalents of hydrochloric acid to form a monohydrochloride salt of said compound of formula (I) or (Ia), followed by crystallizing said monohydrochloride salt, wherein said crystallizing comprises precipitating said monohydrochloride salt in crystalline form from a solvent mixture comprising a protic solvent and a non-polar solvent, most preferably a solvent mixture comprising 2-propanol and heptane.

In one embodiment, there is provided a method according to the first aspect of the invention, further comprising crystallizing the compound of formula (I) or (Ia) and reacting the compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, e.g., about 1.01 molar equivalents of hydrochloric acid to form the monohydrochloride salt of the compound of formula (I) or (Ia).

In one embodiment, there is provided a method according to the first aspect of the invention, further comprising contacting the compound of formula (I) or (Ia) with activated carbon; crystallizing the compound of formula (I) or (Ia); and reacting the compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, e.g., about 1.01 molar equivalents of hydrochloric acid to form the monohydrochloride salt of the compound of formula (I) or (Ia).

In one embodiment, there is provided a method according to a first aspect of the invention, further comprising contacting a compound of formula (I) or (Ia) with activated carbon; crystallizing the compound of formula (I) or (Ia); and reacting the compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, e.g., about 1.01 molar equivalents of hydrochloric acid to form a monohydrochloride salt of the compound of formula (I) or (Ia), wherein the crystallization comprises precipitating the monohydrochloride salt of formula (I) or (Ia) in crystalline form from a solvent mixture comprising a protic solvent and a non-polar solvent, most preferably a solvent mixture comprising 2-propanol and heptane.

In one embodiment, there is provided a method according to the first aspect of the invention, further comprising crystallizing the compound of formula (I) or (Ia) and reacting the compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, e.g., about 1.01 molar equivalents of hydrochloric acid to form a monohydrochloride salt of the compound of formula (I) or (Ia), and subsequently crystallizing the monohydrochloride salt.

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物の塩酸塩を製造するための方法であって、式（Ｉ）の化合物を塩酸、通常は約１．５モル当量以上の塩酸、好ましくは約１．５モル当量以上で約５モル当量未満の塩酸、より好ましくは約２モル当量以上で約３モル当量未満の塩酸、更により好ましくは約２．５モル当量の塩酸と、反応させて、前記式（Ｉ）の化合物の塩酸塩を形成することを含む方法を提供する。 In a second aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, the method comprising reacting a compound of formula (I) with hydrochloric acid, usually at least about 1.5 molar equivalents of hydrochloric acid, preferably at least about 1.5 molar equivalents but less than about 5 molar equivalents of hydrochloric acid, more preferably at least about 2 molar equivalents but less than about 3 molar equivalents of hydrochloric acid, and even more preferably about 2.5 molar equivalents of hydrochloric acid, to form the hydrochloric acid salt of said compound of formula (I).

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物の一塩酸塩を製造するための方法であって、前記式（Ｉ）の化合物を、約１．５モル当量未満の塩酸、通常は約１．５未満で約１モル当量以上の塩酸、好ましくは約１．４モル当量、より好ましくは約１．３モル当量、更により好ましくは約１．２モル当量、なおより好ましくは約１．１モル当量、最も好ましくは約１モル当量、例えば、約１．０１モル当量の塩酸と反応させて、前記式（Ｉ）の化合物の一塩酸塩を形成することを含む方法を提供する。 In a third aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, the method comprising reacting the compound of formula (I) with less than about 1.5 molar equivalents of hydrochloric acid, usually less than about 1.5 and greater than or equal to about 1 molar equivalent of hydrochloric acid, preferably about 1.4 molar equivalents, more preferably about 1.3 molar equivalents, even more preferably about 1.2 molar equivalents, still more preferably about 1.1 molar equivalents, most preferably about 1 molar equivalent, for example about 1.01 molar equivalents of hydrochloric acid to form the monohydrochloride salt of the compound of formula (I).

In one embodiment, there is provided a method according to a third aspect of the present invention, further comprising crystallizing the monohydrochloride salt of the compound of formula (I).

In a preferred embodiment, there is provided a method according to a third aspect of the present invention, further comprising crystallizing the monohydrochloride salt of the compound of formula (I), the crystallization comprising precipitating the monohydrochloride salt in crystalline form from a solvent mixture comprising a protic solvent and a non-polar solvent, most preferably a solvent mixture comprising 2-propanol and heptane.

In one embodiment, there is provided a process according to the third aspect of the invention, wherein the compound of formula (I) is crystallised prior to reacting it with hydrochloric acid.
In one embodiment, there is provided a process according to the third aspect of the invention, wherein the compound of formula (I) is contacted with activated carbon prior to reacting it with hydrochloric acid.

In one embodiment, there is provided a method according to a third aspect of the invention, wherein the compound of formula (I) is crystallized by contacting it with activated carbon and precipitating it in crystalline form from a solvent mixture comprising a protic solvent and a non-polar solvent, most preferably a solvent mixture comprising 2-propanol and heptane, prior to reacting it with hydrochloric acid.

In one embodiment, there is provided a method according to a third aspect of the invention, further comprising crystallizing the monohydrochloride salt of the compound of formula (VI); the compound of formula (I) is crystallized prior to reacting it with hydrochloric acid.

In one embodiment, there is provided a method according to a third aspect of the invention, further comprising crystallizing the monohydrochloride salt of the compound of formula (I); the compound of formula (I) is contacted with carbon on activated charcoal before reacting it with hydrochloric acid.

In a preferred embodiment, a method according to a third aspect of the invention is provided, wherein said reaction of a compound of formula (I) with hydrochloric acid is carried out in a protic solvent, preferably 2-propanol.

More surprisingly, it was found that the monohydrochloride salt of the compound of formula (I) has improved properties, such as a higher melting point and improved solubility in aqueous media, compared to the compound of formula (I) in its free base form. For example, 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride has a melting point of 173° C. (measured by DSC; see FIG. 1), and the respective free base of formula (Ia) has a melting point of only 92° C. (measured by DSC; see FIG. 2). Surprisingly, all attempts to form other acid addition salts failed (Example 5). In addition, attempts to form the respective dihydrochloride salt of the compound of formula (Ia) surprisingly resulted in the formation of a material (Example 5) with two melting points (FIG. 6), suggesting that at least two species were present.

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物の塩酸塩を提供する。 In a fourth aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl.

（上式中、ＸはＯ及びＮＨから選択され；かつ
Ｙ^１、Ｙ^２及びＹ^３は、それぞれ、Ｎ及びＣＨから独立して選択され；かつ
Ｒ^１及びＲ^２は、それぞれ、Ｈ、Ｃ１－Ｃ１０アルキル及びＣ３－Ｃ１２シクロアルキルから独立して選択され；かつ
Ｒ^３及びＲ^４は、それぞれ、Ｈ、ハロゲン及びＣ１－Ｃ１０アルキルから独立して選択される）の化合物の一塩酸塩を提供する。 In a fifth aspect, the present invention provides a compound of formula (I):

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl.

In a preferred embodiment, there is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for said compound of formula (I), X is selected from O and NH.
In particularly preferred embodiments, there are provided the hydrochloride and monohydrochloride salts of the compounds of formula (I) according to the process of the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O.

In a further embodiment, there is provided the method according to the second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^Y1 , ^Y2 and ^Y3 are each selected from N and CH, and wherein at least one of ^Y1 , ^Y2 and Y3 is CH.
In a further embodiment, there is provided the method according to the second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^Y1 , ^Y2 and ^Y3 are each selected from N and CH, and wherein at least one of ^Y1 and Y3 is CH.
In one embodiment, there is provided the method according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^Y1 is selected from N and CH; and ^Y2 and ^Y3 are each CH.
In a preferred embodiment, there is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^Y1 is N; and ^Y2 and ^Y3 are each CH.
In further preferred embodiments, there are provided the methods according to the ^second and third aspects of the invention or the ^{hydrochloride} and monohydrochloride salts according to the fourth and ^fifth aspects of the invention, wherein for the compound of formula (I), each of Y 1 , Y 2 and Y 3 is CH.
In one embodiment, there is provided the hydrochloride and monohydrochloride salts according to the process according to the second and third aspects of the invention or the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^Y1 and ^Y2 are both CH; and ^Y3 is N.
In one embodiment, there is provided the hydrochloride and monohydrochloride salts according to the process according to the second and third aspects of the invention or the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^Y1 and ^Y2 are both N; and ^Y3 is CH.

In one embodiment, there is provided the method according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^R1 and ^R2 are each independently selected from H and C1-C10 alkyl.
In a further embodiment, there is provided the method according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^R1 and ^R2 are each independently selected from H and C3-C12 cycloalkyl.
In a preferred embodiment, there is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for said compound of formula (I), ^{R 1} is H and R 2 is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl.
In a further preferred embodiment, there is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for said compound of formula (I), R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl.

In particularly preferred embodiments, there are provided the methods according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein R ¹ is H and R ² is tert-butyl for the compound of formula (I).

In one embodiment, there is provided the method according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I), ^R3 and ^R4 are each independently selected from H and halogen.

In one embodiment, there is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein for the compound of formula (I) ^R3 and ^R4 are both halogen, preferably fluorine.
In a preferred embodiment, there is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and ^fifth aspects of the invention, wherein for said compound of formula (I), ^R3 is H and R4 is selected from H and halogen, preferably H and fluorine.
In particularly preferred embodiments, there are provided the hydrochloride and monohydrochloride salts of the compounds of formula (I) according to the process of the second and third aspects of the invention or the ^{hydrochloride} and ^{monohydrochloride} salts according to the fourth and fifth aspects of the invention, wherein R3 and R4 are both H for the compounds of formula (I).

In one embodiment, for the compounds of formula (I),
There is provided the process according ^{to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y 1 , Y 2 and Y 3 are each selected from} N and CH, where at least one of Y ¹ , Y 2 and Y 3 is CH; and R 1 and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according ^{to the second} and third aspects of the invention or the hydrochloride and monohydrochloride salts according ^to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each selected from N and CH, where at least one of Y 1 and Y 3 is CH; and R 1 and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R 4 are each independently selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R 1 and R 2 are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y 3 are each CH; and R ¹ is H and R 2 is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R 3 is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and third aspects ^of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ^{3 are each CH; and R 1 is H and R 2 is selected} from H, C3-C8 alkyl and C5-C10 cycloalkyl; and R 3 is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y 3 are each CH; and R ¹ is H and R ² is selected from H and C3-C8 alkyl; and R ³ is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R 2 is selected from H and C5-C10 cycloalkyl; and R ³ is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R 2 is selected from H and C3-C8 alkyl; and R ³ is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C5-C10 cycloalkyl; and R ³ is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R 2 is selected from H and C3-C8 alkyl; and R ³ is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H and C5-C10 cycloalkyl; and R ³ is H and R 4 is selected from H and halogen.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R 3 and R 4 are each independently selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ^{3 are each CH; and R 1 is H and R 2 is selected} from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R 3 and R 4 are each independently selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y 3 are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R 4 is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, ^cyclohexyl and adamantyl; and R ³ is H and R 4 is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according ^to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O; and Y ¹ , Y ² and Y ³ are each CH; and R 1 and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is NH; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, ^cyclohexyl and adamantyl; and R ³ is H and R 4 is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according ^to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is NH; and Y ¹ , Y ² and Y ³ are each CH; and R 1 and R ² are each independently selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, ^iso -propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R 4 is selected from H and F.

In a preferred embodiment, for the compound of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is O; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, ^1,1- dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R 4 is H.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention ^, wherein X is O; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ is H and R 2 is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is NH; and Y ¹ is N; and Y ² and Y ³ are each CH; and R ¹ is H and R ² is selected from H, methyl, ethyl, n-propyl, ^iso -propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R 4 is selected from H and F.

In one embodiment, for the compounds of formula (I),
There is provided the process according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is NH; and Y ¹ , Y ² and Y ^{3 are} each CH; and R 1 is H and R ² is selected from H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, 1,1-dimethylpropyl, 1,1-dimethyl-3,3-dimethylbutyl, 1,1-dimethylbutyl, cyclohexyl and adamantyl; and R ³ is H and R ⁴ is selected from H and F.

In a preferred embodiment, for the compound of formula (I),
There is provided the process ^according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each selected from N and CH; and R ¹ is H and R ² is tert-butyl; and R 3 and R ⁴ are both H.

In a further preferred embodiment, for the compound of formula (I),
There is provided the process according to the ^second and ^third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ is selected from N and CH; and Y ² and Y ³ are each CH; and R 1 is H and R 2 is tert-butyl; and R ³ and R ⁴ are both H.

In a further preferred embodiment, for the compound of formula (I),
There is provided the process ^{according to the second and third aspects of the invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y 1 is N; and Y 2 and Y 3 are each CH; and R 1 is H and R 2} is tert-butyl; and R 3 and R ⁴ are both H.

In a further preferred embodiment, for the compound of formula (I),
There is provided the process according to the second and third aspects of the ^invention or the hydrochloride and monohydrochloride salts according to the fourth and fifth aspects of the invention, wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each CH; and R ¹ is H and R ² is tert-butyl; and R ³ and R 4 are both H.

から選択される、本発明の第二及び第三の態様に係る方法又は本発明の第四及び第五の態様に係る塩酸塩及び一塩酸塩が提供される。 In a particularly preferred embodiment, the compound of formula (I) is

The hydrochloride and monohydrochloride salts according to the process of the second and third aspects of the invention or the fourth and fifth aspects of the invention are provided which are selected from:

In a particularly preferred embodiment, the method according to the second aspect of the invention or the hydrochloride according to the fourth aspect of the invention is provided, in which the compound of formula (I) is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine, i.e., the hydrochloride obtained by the method according to the second aspect of the invention, or the hydrochloride according to the fourth aspect of the invention is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride.

In a further particularly preferred embodiment, the method according to the third aspect of the invention or the monohydrochloride according to the fifth aspect of the invention is provided, in which the compound of formula (I) is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine, i.e. the monohydrochloride obtained by the method according to the third aspect of the invention, or the hydrochloride according to the fifth aspect of the invention is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride.

In a particularly preferred embodiment, there is provided a monohydrochloride salt according to the fifth aspect of the invention, wherein the monohydrochloride salt is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride salt, and has a melting point of about 168°C to about 178°C, preferably about 171°C to about 175°C, most preferably about 173°C (measured using differential scanning calorimetry (DSC)).

In a further particularly preferred embodiment, there is provided a monohydrochloride salt according to the fifth aspect of the present invention, wherein the monohydrochloride salt is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride and has an X-ray powder diffraction pattern measured using CuKα radiation and including the 2θ values shown in FIG. 3.

In a preferred embodiment, there is provided a monohydrochloride according to the fifth aspect of the invention, wherein the monohydrochloride is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride and has 100% purity (>=95% area as measured by HPLC-UV) after 24 months storage at 25°C and 60% rh.

In a further preferred embodiment, there is provided a monohydrochloride salt according to the fifth aspect of the invention, wherein the monohydrochloride salt is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride salt and has a purity of 98.9% (>=95% area as measured by HPLC-UV) after 6 months storage at 40°C and 75% rh.

Use of the hydrochloride and monohydrochloride salts of the invention
In a sixth aspect, the present invention provides the hydrochloride salt of a compound of formula (I) according to the fourth aspect of the invention and embodiments thereof described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride, for use as a medicament.
In a seventh aspect, the present invention provides the monohydrochloride salt of the compound of formula (I) according to the fifth aspect of the invention and the embodiments thereof described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, for use as a medicament.

In an eighth aspect, the present invention provides the hydrochloride salt of a compound of formula (I) according to the fourth aspect of the invention and its embodiments described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride, for use in a method of treatment and/or prophylaxis of cancer.
Also provided is the use of the hydrochloride salt of the compound of formula (I) according to the fourth aspect of the invention and the embodiments thereof described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride, for the manufacture of a medicament for the treatment and/or prevention of cancer.
Also provided is the use of the hydrochloride salt of the compound of formula (I) according to the fourth aspect of the invention and the embodiments thereof described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride, for the treatment and/or prevention of cancer.

In a ninth aspect, the present invention provides the monohydrochloride salt of the compound of formula (I) according to the fifth aspect of the invention and its embodiments described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, for use in a method of treatment and/or prophylaxis of cancer.
Also provided is the use of the monohydrochloride salt of the compound of formula (I) according to the fifth aspect of the invention and the embodiments thereof described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, for the manufacture of a medicament for the treatment and/or prevention of cancer.
Also provided is the use of the monohydrochloride salt of the compound of formula (I) according to the fifth aspect of the invention and the embodiments thereof described above, preferably 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, for the treatment and/or prevention of cancer.

In one embodiment of the fourth and fifth aspects of the present invention, the cancer is a Notch-dependent cancer, preferably a Notch-dependent cancer selected from the group consisting of T-cell-acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), breast cancer, pancreatic cancer, prostate cancer, melanoma, brain tumor, tumor angiogenesis, and colorectal cancer.

The present invention will be described in more detail below, specifically with reference to examples, but the present invention is not limited to these examples.

material:
4-(tert-butyl)-phenol (formula (IIIa)) and 2-chloro-5-nitro-pyridine (formula (IVa)) used in the exemplary embodiment of this invention are commercially available from a variety of sources, for example, Sigma-Aldrich. In general, the building blocks of formulae (III) and (IV) are known and commercially available.
Compounds of formula (II) can be obtained according to general procedure A.
Compounds of formula (I) can be obtained according to general procedure B.
The monohydrochloride salts of compounds of formula (I) described herein can be obtained according to general procedure C.

Equipment:
HPLC:
Instrument: Agilent 1100 series with DAD Software: CDS Chromeleon 6.8
Column: Advanced Materials Technology Halo C18, 2.7 μm, 100 mm x 4.6 mm
Column temperature: 20°C
Mobile phase A: Water Mobile phase B: Acetonitrile Gradient: Time [min] % A % B
0 50 50
5 0 100
5 50 50
7.5 50 50 (equilibrium)
Flow rate: 1.2ml/min Injection volume: 2.0μL
Sample solvent: acetonitrile for compound of formula (Ia)
Acetonitrile/water 3:1 v/v for the monohydrochloride salt of compound of formula (Ia)
Sample concentration: 0.8 mg/mL
Autosampler temperature: 20°C
Detection: UV at 220 nm

XPRD:
X-ray powder diffraction studies were performed using a Bruker D8 Advance using a Cu anode at 40 kV, 40 mA. The software used for data collection was DDiffrac.plus Part 11 (version 3). No background correction or smoothing was applied to the patterns.

General Procedure A: Coupling Compound of formula (III) (1 eq.) and compound of formula (IV) (1 eq.) are dissolved in DMF or DMSO (5 vol.) at room temperature (rt) followed by addition of K ₂ CO ₃ (approximately 1.5 eq.). The mixture is stirred at room temperature until one or preferably both of the compounds of formula (III) and (IV) are fully converted, after which acetic acid (8 vol.) and water (10 vol.) are added. The layers are separated and the organic layer is washed with aqueous NaHCO ₃ (4 vol.) and brine (4 vol.) and dried over anhydrous Na ₂ SO ₄ (0.5-1% w/w). The suspension is filtered and the filter cake (Na2SO4) is washed with ethyl acetate (3 vol.).

Optional Crystallization:
The combined filtrates are concentrated to about half their volume (i.e., about 6 volumes of ethyl acetate are distilled off). Subsequently, heptane (10 volumes) is added at Tout=50° C. and a portion of the solvent (about 10 volumes) is distilled off. The resulting concentrated solution is cooled to Tout=−20° C. to obtain a suspension. The suspension is filtered and the filter cake is washed with cold heptane (4 volumes) and dried on a rotary evaporator to obtain the respective nitro-diaryl compound of formula (II).

General Procedure B: Hydrogenation In an autoclave, the compound of formula (II) obtained according to general procedure A is dissolved in ethyl acetate (5 volumes). A suspension of palladium on activated carbon (preferably with a Pd content of 5% w/w; preferably with about 1.25 mol% Pd) in ethyl acetate (1 volume) is then added to the solution at room temperature via a funnel, and the funnel is rinsed with ethyl acetate (3 volumes). The autoclave is purged with hydrogen, and the suspension is then stirred at room temperature under a hydrogen pressure of 0.5 bar until complete conversion at room temperature. The suspension is then filtered, and the filter cake is rinsed with ethyl acetate (3 volumes).

Work-up with optional crystallization:
The filtrate is concentrated under reduced pressure to about half of its volume. Activated charcoal is then added at room temperature and the resulting suspension is stirred at room temperature. The suspension is then filtered and the filter cake is washed with ethyl acetate (2 x 2 volumes). The combined filtrate is concentrated under reduced pressure to about 1/3 of the initial volume and heptane (7 volumes) is added at Tout = 40°C, after which about half of the solvent is distilled off. The concentrated solution is cooled to Tout = -20°C to obtain a suspension which is further cooled to Tout = -24°C. The suspension is then filtered and the filter cake is washed with cold heptane (3 volumes) and dried on the filter overnight to obtain the respective amino-diaryl compound of formula (I).

General Procedure C: Salt Formation The compound of formula (I) is dissolved in 2-propanol (4 volumes). The solution is heated to Tout=40° C. and 5-6N HCl in 2-propanol (about 1.0 eq.) is added dropwise at Tout=40° C. (Ti _max =44.9° C.). Then, optionally, a seed of the monohydrochloride salt of the compound of formula (I) (0.1% w/w) is added. The (seeding) mixture is stirred at Ti=40° C. for about 0.5 hours to obtain a suspension. Heptane (4 volumes) is added at Ti=40° C. and the suspension is further warmed to Ti=45° C. A second portion of heptane (8 volumes) is added. The mixture is then warmed to Tout=55° C. and stirring is continued at this temperature for about 1 hour.

Work-up:
The suspension is cooled to Ti=13° C. over about 16 hours, then further cooled to Ti=0° C. over about 30 minutes and stirred at Ti=0° C. for 1 hour. The suspension is then filtered and the filter cake is washed with a 10:1 mixture of heptane and 2-propanol (3 volumes). The filter cake is dried on a rotary evaporator (Tout=50° C., <10 mbar) for 3 days to obtain the monohydrochloride salt of the compound of formula (I), typically as a colorless crystalline solid.

Example 1A: 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (Formula (IIa))
According to general procedure A, 4-(tert-butyl)-phenol (Formula (IIIa), 3.98 kg) and 2-chloro-5-nitro-pyridine (Formula (IVa), 4.13 kg) were dissolved in DMSO (21 L) at room temperature (rt) followed by the addition of K ₂ CO ₃ (5.41 kg) over 17 min at room temperature. The mixture was stirred at room temperature for 17.25 h after which ethyl acetate (33 L) and water (20 L) were added. The resulting biphasic mixture was stirred for 35 min and allowed to stand for an additional 35 min before the layers were separated. The organic layer was washed with aqueous NaHCO ₃ (8% w/w, 16.5 L) and brine (16.5 L) and dried over anhydrous Na ₂ SO ₄ (2.5 kg). The suspension was filtered and the filter cake (Na ₂ SO ₄ ) was washed with ethyl acetate (13 L). The combined filtrates were then concentrated under reduced pressure (25 L of ethyl acetate was distilled off). Subsequently, heptane (mixture of isomers, 41 L) was added at Tout=50° C. over 7 min and 42 L of solvent was distilled off under reduced pressure. The resulting yellow solution was cooled to Tout=−20° C. over 20 h and stirred at that temperature for 65 min to obtain a suspension. The suspension was filtered and the filter cake was washed with cold heptane (mixture of isomers, 16.5 L) and dried overnight on a rotary evaporator to obtain 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (Formula (IIa), 6.2 kg, 87%) as a white solid.

Example 1B: 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (Formula (IIa))
According to general procedure A, 4-(tert-butyl)-phenol (Formula (IIIa), 7.94 kg) and 2-chloro-5-nitro-pyridine (Formula (Va), 8.36 kg) were dissolved in DMSO (42 L) at room temperature (rt), followed by the addition of K ₂ CO ₃ (10.96 kg) over 12 min at room temperature. The mixture was stirred at room temperature for 21.5 h, after which ethyl acetate (66 L) and water (42 L) were added. The resulting biphasic mixture was stirred for 68 min and allowed to stand for an additional 2 h before the layers were separated. The organic layer was washed with aqueous NaHCO ₃ (8% w/w, 33 L) and brine (33 L) and dried over anhydrous Na ₂ SO ₄ (5 kg). The suspension was filtered and the filter cake (Na ₂ SO ₄ ) was washed with ethyl acetate (25 L). The combined filtrate was then concentrated under reduced pressure (48 L of ethyl acetate was distilled off). Subsequently, heptane (mixture of isomers, 84 L) was added at Tout=50° C. over 67 min and 79 L of solvent was distilled off under reduced pressure. The resulting yellow solution was cooled to Tout=−20° C. over 20 h and stirred at that temperature for 61 min to give a suspension. The suspension was filtered and the filter cake was washed with cold heptane (mixture of isomers, 33 L) and dried overnight on a rotary evaporator to give 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa), 70% in two portions of 4.96 and 5.06 kg) as a white solid. However, the material that was coated on the vessel and dissolved in 20 L of ethyl acetate combined with the mother liquor was retransferred to a solvent switch from ethyl acetate to heptane according to the general process to give a third portion of 3.59 kg (23%) as a white solid. The overall yield increased to 93% in stage 1.

Example 2 (Comparative Example): 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia)) obtained by the method described in WO 2013/093885
2-(4-(tert-butyl)phenoxy)-5-nitropyridine (Formula (IIa), 8.6 g) and palladium on activated carbon (2.35 g, 10% wt/wt palladium) in MeOH (86 mL) were stirred at room temperature under _H2 atmosphere (0.5 bar) for 2 h to give 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia)). However, N-methylated by-products were observed by HPLC and a Pd content of 6.9 ppm was detected by elemental analysis.

Example 3A: 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia))
According to general procedure B, 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa), 1.2 kg) was dissolved in ethyl acetate (6 L) in an autoclave. A suspension of palladium on activated carbon (119 g, 5% wt/wt palladium) in ethyl acetate (1.2 L) was then added to the solution via a funnel at room temperature, and the funnel was rinsed with ethyl acetate (3.6 L). The autoclave was purged with hydrogen (5 bar) and then the suspension was stirred (832 rpm) under a hydrogen pressure of 0.5 bar at room temperature until complete conversion (2 h 20 min). The suspension was then filtered and the filter cake was rinsed with ethyl acetate (3.6 L).
Work-up: In this procedure five hydrogenation runs were combined and treated according to the general procedure.
The filtrates (from 5 experiments) were combined and concentrated under reduced pressure (74 L of ethyl acetate were distilled off). Then, activated carbon (605 g) was added at Tout=25° C. and the resulting suspension was stirred at Tout=25° C. for 1 h 10 min. The suspension was then filtered and the filter cake was washed with ethyl acetate (2×12 L). The combined filtrates were concentrated under reduced pressure (42 L of ethyl acetate were distilled off), heptane (mixture of isomers, 42 L) was added at Tout=40° C. over 12 min, after which 36 L of solvent were distilled off under reduced pressure. The concentrated solution was cooled to Tout=−20° C. over 6 h to give a suspension, which was stirred at Tout=−24° C. for another 1 h. The suspension was then filtered and the filter cake was washed with cold heptane (isomer mixture, 19 L) and dried on the filter overnight to give 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia), 4.95 kg, 91%) as a reddish solid.

Example 3B: 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia))
According to general procedure B, 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa), 50 g) was dissolved in 2-propanol (0.4 L) in an autoclave. A suspension of palladium on activated carbon (5 g, 5% wt/wt palladium) in 2-propanol (25 mL) was then added to the solution via a funnel at room temperature, and the funnel was rinsed with 2-propanol (25 mL). The autoclave was purged with hydrogen (5 bar) and then the suspension was stirred (832 rpm) under a hydrogen pressure of 0.1 bar at room temperature until complete conversion (7 h 30 min). The suspension was then filtered and the filter cake was rinsed with 2-propanol (0.2 L).
Work-up: The filtrate was concentrated under reduced pressure (0.65 L of 2-propanol was distilled off) and 6-(4-(tert-butyl)phenoxy)pyridin-3-amine was isolated as a solid.

Example 4: 6-(4-(tert-Butyl)phenoxy)pyridin-3-amine monohydrochloride According to general procedure C, 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia), 4.95 kg) was dissolved in 2-propanol (20 L). The solution was heated to Tout=40° C. and 5-6N HCl in 2-propanol (3.7 L, 1.01 eq.) was added dropwise over 20 min at Tout=40° C. (Ti _max =44.9° C.). A seed of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride (5 g) was added and the seeded mixture was stirred at Ti=40° C. for 0.5 h to give a suspension. Heptane (isomer mixture, 20 L) was added over 33 min at Ti=40° C. and the suspension was further warmed to Ti=45° C. A second portion of heptane (isomer mixture, 40 L) was added dropwise over 54 min. The mixture was then warmed to Tout=55° C. and stirring was continued at this temperature for 1 h.
Work-up:
The suspension was cooled to Ti=13° C. over 16 h, then further cooled to Ti=0° C. over 30 min and stirred at Ti=0° C. for 1 h. The suspension was then filtered and the filter cake was washed with a 10:1 mixture of heptane (isomer mixture) and 2-propanol (2×16.5 L). The filter cake was dried on a rotary evaporator (Tout=50° C., <10 mbar) for 3 days to give the title compound as a colorless crystalline solid (5.02 kg, 88%).

Example 5: Salt formation with 6-(4-(tert-butyl)phenoxy)pyridin-3-amine The formation of different salts was examined according to the procedure shown in Table 1 below.

Example 6: Forced Decomposition of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine Monohydrochloride Equipment:
Light stability chamber: Solarbox 1500e
Oven: Salvis vacuum drying oven VC-20
Heating unit: lkamag RET-GS with lkamag ETS SD and stainless steel heating block
Vials: Supelco V-vials with screw cap airtight vials with PTFE septa Agilent 10mL HS-GC clear glass vials with crimped caps with incompatible PTFE septa Quartz glass cuvettes: Hellma precision cuvettes Suprasil, type 117.100-QS, 10mm path length, screw capped with silicone septa HPLC: As above

Analysis method:
The HPLC test method described above was used to determine the chemical analysis and purity of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride before the forced degradation experiment, and the area % amounts of individual impurities and decomposition products in the 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride samples obtained from the degradation experiment.
The identity of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride was determined by comparison of retention time with a reference.
The chemical analysis and purity of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride were determined using HPLC with UV detection at 220 nm utilizing the area normalization method for purity determination and external standard calibration for chemical analysis determination. During all experiments, UV spectra were recorded from 200 nm to 950 nm and the peak purity of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride was also assessed.
Only a single determination was performed for each test condition.
For each test condition described below, one sample was prepared and analyzed according to the HPLC method.

1. Thermally Stressed Solid State Approximately 20.4 mg and 50.1 mg of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride were weighed into Supelco V-vials. The vials were closed with screw caps and stored in the heating block of a heating unit operated at 100° C.±5° C. for 20 hours (20 mg sample) and 68 hours (50 mg sample), respectively.
After storage at 100°C for the intended time, each sample was cooled to room temperature and the contents of the vial were dissolved in approximately 4 mL of sample solvent (acetonitrile/water 3:1 v/v). The resulting solution was quantitatively transferred to a 25 mL volumetric flask (20 mg sample) or a 50 mL volumetric flask (50 mg sample), respectively. The vial was then rinsed three times with approximately 4 mL of sample solvent, each time transferring the contents of the vial to the 25 mL volumetric flask again. After filling the flask to the brim with sample solvent and shaking vigorously, an aliquot of this solution was transferred to an HPLC vial for analysis.
Results: 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride is stable in the solid state at 100° C. No significant changes in purity and purity profile were observed after storage at 100° C. for 68 hours. The observed decreases in chemical analyses were within the accepted variation range of the method (±2%).

2. Solid state stressed by UV/VIS radiation Two samples of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, 20.23 mg and 20.17 mg, respectively, were weighed into quartz glass cuvettes. Both cuvettes were closed with screw caps. One of the cuvettes was protected by wrapping it in aluminum foil. This sample served as a dark control. Both cuvettes were placed next to each other in a photostable chamber and exposed to UV/VIS radiation applying an energy of 500 W/ ^m2 until a total illumination of 1200 kLux·h was reached, according to guidelines [4]. After exposure to UV/VIS radiation with an illumination of 1200 kLux·h, the samples were allowed to return to room temperature and the contents of the cuvettes were dissolved in approximately 2 mL of sample solvent (acetonitrile/water 3:1 v/v). The resulting solution was quantitatively transferred into a 25 mL volumetric flask. The cuvette was then rinsed five times with approximately 2 mL of sample solvent, each time transferring the contents of the cuvette again to a 25 mL volumetric flask. After filling the flask to the brim with sample solvent and shaking well, an aliquot of this solution was transferred to an HPLC vial for analysis.
Results: In the solid state 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride is stable to UV/VIS radiation. After irradiation with 1200 kLux·h and an energy input of 500 W/ ^m2 , the purity decreased by 0.6 area %, which was mainly related to the appearance of two unknown impurities. The observed decrease in the chemical analysis of 2.1% w/w was not related to UV/VIS radiation, since the chemical analysis of the dark control had a similar value (a decrease of 2.4% w/w).

定められた条件で意図された時間保管した後、各サンプルを室温まで冷却した。次に、２．０ｍＬの０．１ＭのＨＣｌ水溶液を添加してサンプルを中和した。各サンプルについて、バイアルの内容物を２５ｍＬの容量フラスコに定量的に移した。次に、バイアルを約５ｍＬのサンプル溶媒（アセトニトリル／水３：１ｖ／ｖ）で３回リンスし、そのたびにバイアルの内容物をまた２５ｍＬの容量フラスコに移した。フラスコをサンプル溶媒でいっぱいに満たしてよく振とうした後、この溶液のアリコートを分析のためにＨＰＬＣバイアルに移した。
記録された全てのクロマトグラムを、分析法［１］に従って、同一性、化学分析値、及び純度について評価した。加えて、安定性サンプルのクロマトグラムにおいてピーク純度を評価した。各分析シーケンスについて、分析法［１］で特定されているようにＳＳＴを実施した。分析シーケンスの各々について、全てのＳＳＴ基準が満たされた。 3. Alkaline and Heat Stress in Aqueous Solution Approximately 20 mg (4x) of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride was weighed into a 10 mL GC-HS vial and 2.0 mL of 0.1 M aqueous NaOH was added. Four vials were crimped and shaken. Two vials were stored in an oven operated at 60°C ± 5°C and two were stored in an oven operated at 90°C ± 5°C. In addition, a blank sample was prepared by transferring 2.0 mL of 0.1 M aqueous NaOH to a 10 mL GC-HS vial. After crimping, the vial containing the blank was stored in an oven operated at 90°C ± 5°C. The test conditions are summarized in Table 2.

After storage at the prescribed conditions for the intended time, each sample was cooled to room temperature. Then, 2.0 mL of 0.1 M aqueous HCl was added to neutralize the sample. For each sample, the contents of the vial were quantitatively transferred to a 25 mL volumetric flask. The vial was then rinsed three times with approximately 5 mL of sample solvent (acetonitrile/water 3:1 v/v), each time transferring the contents of the vial to the 25 mL volumetric flask again. After filling the flask to the brim with sample solvent and shaking well, an aliquot of this solution was transferred to an HPLC vial for analysis.
All recorded chromatograms were evaluated for identity, chemical analysis, and purity according to analytical method [1]. In addition, peak purity was evaluated in the chromatograms of the stability samples. For each analytical sequence, SST was performed as specified in analytical method [1]. All SST criteria were met for each of the analytical sequences.

Example 7 Solubility of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride vs. 6-(4-(tert-butyl)phenoxy)pyridin-3-amine The aqueous solubility of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia)) and its monohydrochloride salt, i.e. 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, was evaluated at various pH values according to Tables 3 and 4. The aqueous solubility of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia)) according to Table 3 was analyzed as follows: 500 mg of the free base was placed in 14 mL of acidic medium at pH=2, 4, neutral pH=7 and basic pH=10 to obtain a suspension within the calculated concentration of about 35 mg/mL. The solubility of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride in water according to Table 4 was analyzed as follows: 100 mg of each HCl salt was placed in acidic media of pH=2 and 4 and in neutral media of pH=7 to give solutions. The most important observation was that in the neutral solution of pH=7, the pH was reduced to pH=1 by placing 100 mg of HCl salt.

6-(4-(tert-butyl)phenoxy)pyridin-3-amine (Formula (Ia)) was found to be very poorly soluble in water regardless of pH. The solubility limit of compound of formula (Ia) in 0.01% HCl was determined to be 100 mg in 190 mL (0.53 mg/mL). In contrast, the monohydrochloride salt of compound of formula (Ia) was found to be highly soluble in water.

Example 8: Stability study of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride:
Two different types of stability studies were performed on 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride, including short-term and long-term stability studies at 25° C. (RH, 60%), −5° C. and −20° C. for 36 months and an accelerated study at 40° C. (RH, 75%) for 6 months, respectively. The results of these studies are shown in Tables 7-14 below. With regard to analytical determinations, six tests were included including appearance, free base chemical analysis average and purity average, water, IR and XRPD. Appearance was determined by visual inspection. The product should be a white or off-white powder. Water content was determined according to USP <921> coulometric analysis. IR spectroscopy characterization of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride was performed according to USP <197>, comparing the spectrum obtained with that of a reference standard. X-ray powder diffraction (XRPD) was performed according to USP <941> against a reference XRPD spectrum. Purity and chemical analysis of the free base was performed by HPLC-UV. Two methods were used. The mobile phase for the first method was water and acetonitrile. The mobile phase for the second method was water (0.5 mL trifluoroacetic acid added to 1000 mL water) and acetonitrile (0.4 mL trifluoroacetic acid added to 1000 mL acetonitrile). The equipment and chromatographic conditions for the identification and determination of purity and chemical analysis of 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride by HPLC-UV according to the first and second methods, respectively, are shown in Tables 5 and 6.

Claims (22)

Formula (I)

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, comprising the steps of:
Formula (II)

wherein X is selected from O and NH; and Y ¹ , Y ² , and Y ³ are each independently selected from N and CH; and R ¹¹ and R ²² are each independently selected from H, C1-C10 alkyl, and C3-C12 cycloalkyl; and R ³³ and R ⁴⁴ are each independently selected from H, halogen, and C1-C10 alkyl.
with hydrogen in the presence of a palladium catalyst and a solvent which is a polar aprotic solvent or a C3-C10 alcohol to form a compound of formula (I). The method of claim 1, wherein the palladium catalyst is palladium on activated carbon. The method of claim 1 or 2, wherein the palladium catalyst is present in an amount of less than 7 mol%. The method according to any one of claims 1 to 3, wherein the solvent is selected from 2-propanol, acetone, 2-butanone, 3-methyl-2-butanone, cyclohexanone, acetonitrile, chlorobenzene, methylene chloride, chloroform, trichloroethane, ethylene chloride, benzaldehyde, sulfolane, ethyl acetate, propyl acetate, amyl acetate, dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, diethyl carbonate, propylene carbonate, ethylene carbonate, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and mixtures thereof. The method of any one of claims 1 to 3, wherein the solvent is ethyl acetate. The method of any one of claims 1 to 5, further comprising contacting the compound of formula (I) with activated carbon. The method of any one of claims 1 to 6, further comprising crystallizing the compound of formula (I). The compound of formula (I) is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine (formula (Ia))

and the compound of formula (II) is 2-(4-(tert-butyl)phenoxy)-5-nitropyridine (formula (IIa))

The method according to any one of claims 1 to 7, wherein The method of any one of claims 1 to 8, further comprising reacting a compound of formula (I) or (Ia) with hydrochloric acid to form a hydrochloride salt of the compound of formula (I) or (Ia). The method of any one of claims 1 to 8, further comprising reacting the compound of formula (I) or (Ia) with less than about 1.5 molar equivalents of hydrochloric acid to form the monohydrochloride salt of the compound of formula (I) or (Ia). The method of claim 11, further comprising crystallizing the monohydrochloride salt. The compound of formula (II) is represented by formula (III)

wherein X ¹ is selected from OH and NH ₂ ; and R ¹¹ and R ²² are each independently selected from H, C1-C10 alkyl, and C3-C12 cycloalkyl.
With a compound of formula (IV)

wherein LG is a leaving group; and Y ¹ , Y ² , and Y ³ are each independently selected from N and CH; and R ³³ and R ⁴⁴ are each independently selected from H, halogen, and C1-C10 alkyl.
in the presence of a base to form a compound of formula (II)
wherein X is O or NH; and R ¹¹ and R ²² are as defined for compounds of formula (III); and R ³³ , R ⁴⁴ , Y ¹ , Y ² and Y ³ are as defined for compounds of formula (IV).
12. The process according to claim 1 , wherein the compound is obtained by a process comprising: forming a compound of formula (II) of formula (II); and optionally further comprising crystallizing the starting material of formula (II). Formula (I)

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, the process comprising reacting said compound of formula (I) with hydrochloric acid to form the hydrochloride salt of said compound of formula (I). Formula (I)

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl, the process comprising reacting said compound of formula (I) with less than 1.5 molar equivalents of hydrochloric acid to form the monohydrochloride salt of said compound of formula (I). Formula (I)

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl. Formula (I)

wherein X is selected from O and NH; and Y ¹ , Y ² and Y ³ are each independently selected from N and CH; and R ¹ and R ² are each independently selected from H, C1-C10 alkyl and C3-C12 cycloalkyl; and R ³ and R ⁴ are each independently selected from H, halogen and C1-C10 alkyl. The method of claim 13 or the hydrochloride of claim 15, wherein the hydrochloride is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride. The method of claim 14 or the monohydrochloride of claim 16, wherein the monohydrochloride is 6-(4-(tert-butyl)phenoxy)pyridin-3-amine monohydrochloride. The hydrochloride salt of claim 15 or 17 for use as a medicine. The monohydrochloride salt of claim 16 or 18 for use as a medicine. The hydrochloride salt of claim 15 or 17 for use in a method for treating and/or preventing cancer. The monohydrochloride salt of claim 16 or 18 for use in a method for the treatment and/or prevention of cancer.

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